Discovery of novel 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as potent Na(v)1.1 activators

摘要

The voltage-gated sodium channel, Na(v)1.1, is predominantly expressed in parvalbumin-positive fast spiking interneurons and has been genetically linked to Dravet syndrome. Starting from a high throughput screening hit isoxazole derivative 5, modifications of 5 via combinations of IonWorks and Q-patch assays successfully identified the nicotinamide derivative 4. Its increasing decay time constant (tau) of Na(v)1.1 currents at 0.03 mu M along with significant selectivity against Na(v)1.2, Na(v)1.5, and Na(v)1.6 and acceptable brain exposure in mice was observed. Compound 4 is a promising Na(v)1.1 activator that can be used to analyze pathophysiological functions of the Na(v)1.1 channel towards treating various central nervous system diseases.